Protein kinases, a class of enzymes that phosphorylate proteins, are involved in a wide variety of processes including the cell cycle and cellular signal pathways. Examples of protein kinases include p38 kinases and LIM kinases.
A large number of cytokines participate in the inflammatory response, including IL-1, IL-6, IL-8, and TNF-α. Overproduction of cytokines such as IL-1 and TNF-α are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others [Henry et al., Drugs Fut., 24:1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6:807-823 (1999)]. Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases, such as, for example, monoclonal antibody to TNF-α (Enbrel) [Rankin et al., Br. J. Rheumatol., 34:334-342 (1995)], and soluble TNF-α receptor-Fc fusion protein (Etanercept) [Moreland et al., Ann. Intern. Med., 130:478-486 (1999)].
The biosynthesis of TNF-α occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TNF-α production include the mitogen-activated protein (MAP) kinases, a family of Ser/Thr protein kinases that activate their substrates by phosphorylation. The MAP kinases are activated in response to various stress stimuli, including but not limited to proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock.
One important MAP kinase is p38 kinase, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) or IK. Activation of p38 requires dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes. There are four known isoforms of p38, i.e., p38-α, p38β, p38γ, and p38δ. The α and β isoforms are expressed in inflammatory cells and are key mediators of TNF-α production. Inhibiting the p38α and β enzymes in cells results in reduced levels of TNF-α expression. Also, administering p38α and β inhibitors in animal models of inflammatory disease has proven that such inhibitors are effective in treating those diseases. Accordingly, the p38 enzymes serve an important role in inflammatory processes mediated by IL-1 and TNF-α.
Compounds that reportedly inhibit p38 kinase and cytokines such as IL-1 and TNF-α for use in treating inflammatory diseases are disclosed in U.S. Pat. Nos. 6,277,989 and 6,130,235 to Scios, Inc; U.S. Pat. Nos. 6,147,080 and 5,945,418 to Vertex Pharmaceuticals Inc; U.S. Pat. Nos. 6,251,914, 5,977,103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Pat. Nos. 5,932,576 and 6,087,496 to G. D. Searle & Co.; WO 00/56738 and WO 01/27089 to Astra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazoline derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship between p38 kinase inhibitors); WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors), U.S. Pat. application publication No. US2002/0010170 A1, U.S. Pat. No. 6,670,357 (pyrrolotriazine compounds useful as p38 kinase inhibitors); WO 03/0099820 (aniline-substituted pyrazolo-pyrimidine compounds useful for treating p38 kinase-associated conditions); and WO 04/071440 (thiazolyl-based compounds useful for treating p38 kinase-associated conditions).
The metastasis of cancer cells involves the modulation of signal pathways that regulate the actin cytoskeleton. Cofilin, an actin binding protein, acts as a regulator of actin dynamics by promoting F-actin depolymerization. Kinases, such as LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2), have been identified as participating in signal pathways affecting actin dynamics by deactivating cofilin. Over expression of LIMK1 has been found in invasive breast and prostate cancer cell lines [Yoshioka et al., Proc. Nat. Acad. Sci. 100(12) 7247-7252 (2003); Davila et al., J. Biol. Chem., 278(38) 36868-36875 (2003)]. Suppression of LIMK 2 expression has been found to limit migration of human fibrosarcoma cells [Suyama et al., J. Gene Med., 6:357-363 (2004). Accordingly, the inhibition of LIMK1 and/or LIMK2 enzymes have been suggested as targets for treating cancer, including reduction or prevention of metastasis.
The present invention provides certain phenyl-substituted pyrimidine compounds useful as kinase inhibitors, particularly kinases p38α and β, and/or LIM kinases, such as LIM kinase 1 and/or LIM kinase 2. JP2001089452 to Sankyo Co. Ltd, published Apr. 3, 2001 in Japanese, discloses certain phenyl-substituted pyrimidine compounds. JP2003206230 to Yamanouchi Pharmaceutical Co. Ltd., published Jul. 22, 2003 in Japanese, discloses cyano heterocyclic compounds, including certain phenyl-substituted cyano pyrimidine compounds, as a calcium channel blocking-drug. A method of treating a cyclin-dependent kinases (CDK) dependent or sensitive disorder and a method of treating viral disorders using 2-substituted 4-heteroarylpyrimidines, are disclosed in U.S. Pat. No. 6,531,479 and WO 2004/043467, respectively, to Cyclacel Ltd. Pyrazole compounds, including certain phenyl-substituted pyrimidine compounds, useful as protein kinase inhibitors, are disclosed in WO 02/22607 to Vertex Pharmaceuticals Incorporated. Each of the patent applications, patents, and publications referred to herein is incorporated herein by reference.